title: Molecular and biologic analysis of histone deacetylase inhibitors with diverse specificities.
abstract: Histone deacetylase inhibitors (HDACi) are anticancer agents that induce hyperacetylation of histones, resulting in chromatin remodeling and transcriptional changes. In addition, nonhistone proteins, such as the chaperone protein Hsp90, are functionally regulated through hyperacetylation mediated by HDACis. Histone acetylation is thought to be primarily regulated by HDACs 1, 2, and 3, whereas the acetylation of Hsp90 has been proposed to be specifically regulated through HDAC6. We compared the molecular and biologic effects induced by an HDACi with broad HDAC specificity (vorinostat) with agents that predominantly inhibited selected class I HDACs (MRLB-223 and romidepsin). MRLB-223, a potent inhibitor of HDACs 1 and 2, killed tumor cells using the same apoptotic pathways as the HDAC 1, 2, 3, 6, and 8 inhibitor vorinostat. However, vorinostat induced histone hyperacetylation and killed tumor cells more rapidly than MRLB-223 and had greater therapeutic efficacy in vivo. FDCP-1 cells dependent on the Hsp90 client protein Bcr-Abl for survival, were killed by all HDACis tested, concomitant with caspase-dependent degradation of Bcr-Abl. These studies provide evidence that inhibition of HDAC6 and degradation of Bcr-Abl following hyperacetylation of Hsp90 is likely not a major mechanism of action of HDACis as had been previously posited.
authors.affiliation: Corresponding Author: Ricky Johnstone, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3002, Australia. ricky.johnstone@petermac.org.
authors.forename: Andrea
authors.initials: A
authors.lastname: Newbold
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Matthews
authors.forename: Michael
authors.initials: M
authors.lastname: Bots
authors.forename: Leonie A
authors.initials: LA
authors.lastname: Cluse
authors.forename: Christopher J P
authors.initials: CJ
authors.lastname: Clarke
authors.forename: Kellie-Marie
authors.initials: KM
authors.lastname: Banks
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Bolden
authors.forename: Ailsa J
authors.initials: AJ
authors.lastname: Christiansen
authors.forename: Ross A
authors.initials: RA
authors.lastname: Dickins
authors.forename: Claudia
authors.initials: C
authors.lastname: Miccolo
authors.forename: Susanna
authors.initials: S
authors.lastname: Chiocca
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Kral
authors.forename: Nicole D
authors.initials: ND
authors.lastname: Ozerova
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Miller
authors.forename: Joey L
authors.initials: JL
authors.lastname: Methot
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Richon
authors.forename: J Paul
authors.initials: JP
authors.lastname: Secrist
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D016044:Fusion Proteins, bcr-abl; C433811:HDAC6 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases